This program will build on the progress of the past 3 years of interaction among cell biologists, biochemists, molecular biologists and clinicians to provide new postulates to explain key events in human colon cancer etiology and behavior. Experimental questions based on clinical phenomena will focus on the following major themes: (1) What is the function of CEA, particularly in relation to colorectal cancer differentiation and site-specific metastasis? (2) What is the relationship between specific laminin binding proteins, colorectal carcinoma differentiation, and metastasis (3) Is expression of markers of gastrointestinal epithelial differentiation (such as fimbrin, villin, 110K) altered during or after human colorectal cancer transformation? (4) Can genes that influence our candidate differentiation/transformation markers be manipulated in novel, reconstitution models that will allow us to link predicted biochemical and molecular changes in gastrointestinal epithelium to morphologic criteria of premalignant or malignant colonic mucosa? (5) Can the availability of well defined, fresh human tissue samples (normal colon, primary colon cancer, lymph node metastases, or distant metastases from the same patient) allow us to prepare cDNA libraries and to select cDNA clones that will distinguish among various forms of colorectal cancer as well as normal colon, and finally (6) Can the reagents (monoclonal antibodies, oligonucleotide probes) produced against our novel molecular targets be applied directly to fresh and/or archival human tissue in order to enhance our ability to predict the aggressiveness of colon and rectum cancers? The proposed studies will expand the successful investigations of the past 3 years to provide new prognostic criteria for human colon and rectum cancer. Better understanding of mechanisms involved in invasion and site-specific metastasis will allow new therapy avenues to be postulated. Basic science questions derived from strong interaction between clinic and research lab; proven availability of patient resources; establishment of successful tissue and sera bank networks; our record of interaction among Project Leaders as well as Core; involvement of important local medical institutions in the project; and our recent connection with a multi-institutional, national therapy trial group, are the foundations for this revised 5 year renewal request.